c-Jun enhances intestinal epithelial restitution after wounding by increasing phospholipase C-γ1 transcription

Am J Physiol Cell Physiol. 2017 Apr 1;312(4):C367-C375. doi: 10.1152/ajpcell.00330.2016. Epub 2017 Jan 18.

Abstract

c-Jun is an activating protein 1 (AP-1) transcription factor and implicated in many aspects of cellular functions, but its exact role in the regulation of early intestinal epithelial restitution after injury remains largely unknown. Phospholipase C-γ1 (PLCγ1) catalyzes hydrolysis of phosphatidylinositol 4,5 biphosphate into the second messenger diacylglycerol and inositol 1,4,5 triphosphate, coordinates Ca2+ store mobilization, and regulates cell migration and proliferation in response to stress. Here we reported that c-Jun upregulates PLCγ1 expression and enhances PLCγ1-induced Ca2+ signaling, thus promoting intestinal epithelial restitution after wounding. Ectopically expressed c-Jun increased PLCγ1 expression at the transcription level, and this stimulation is mediated by directly interacting with AP-1 and CCAAT-enhancer-binding protein (C/EBP) binding sites that are located at the proximal region of the rat PLCγ1 promoter. Increased levels of PLCγ1 by c-Jun elevated cytosolic free Ca2+ concentration and stimulated intestinal epithelial cell migration over the denuded area after wounding. The c-Jun-mediated PLCγ1/Ca2+ signal also plays an important role in polyamine-induced cell migration after wounding because increased c-Jun rescued Ca2+ influx and cell migration in polyamine-deficient cells. These findings indicate that c-Jun induces PLCγ1 expression transcriptionally and enhances rapid epithelial restitution after injury by activating Ca2+ signal.

Keywords: AP-1 gene transcription; Ca2+ influx; epithelial restitution; intestinal epithelial cells; polyamines.

MeSH terms

  • Animals
  • Calcium Signaling
  • Cell Line
  • Gene Expression Regulation, Enzymologic
  • Intestinal Mucosa / injuries*
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Intestinal Perforation / metabolism*
  • Phospholipase C gamma / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Rats
  • Transcription, Genetic
  • Up-Regulation
  • Wound Healing / physiology*

Substances

  • Proto-Oncogene Proteins c-jun
  • Phospholipase C gamma
  • phospholipase Cgamma1, rat